The present invention relates to novel pyrido-thieno-diazepines, their preparation process and the pharmaceutical compositions containing them. These diazepines are particularly useful for treating pathological states or diseases in which one (or more) somatostatin receptors are involved.
Somatostatin (SST) was isolated for the first time as a factor inhibiting the secretion of growth hormone (Brazeau P. et al., Science 1973, 179, 77-79). This substance is known in two forms somatostatin 14 and somatostatin 28 and is widely distributed in the animal kingdom and in man. The peptides of this family also operate as neurotransmitters in the brain (hypothalamus, sensitive neurons, cerebral cortex) (Reisine T. et al., Neuroscience 1995, 67, 777-790; Reisine et al., Endocrinology 1995, 16:427-442) and in the endocrine organs (pancreas, intestine, kidney, salivary glands, thyroid C cells etc.). The bioactivity of somatostatin depends directly on a family of five recently cloned receptors.
Among the pathological disorders associated with somatostatin (Moreau J. P. et al., Life Sciences 1987, 40, 419; Harris A. G. et al., The European Journal of Medicine, 1993, 2, 97-105), there can be mentioned for example: acromgalia, hypophyseal adenomas which do not secrete growth hormones, hypophyseal adenomas which secrete thyreostimulin, Cushing""s disease, gonadotrophinomas and prolactinomas, catabolic side-effects of glucocorticoids, hypophyseal adenomas without endocrinic action, insulin dependent diabetes, diabetic retinopathy, diabetic nephropathy, hyperthyroidism, gigantism, endocrinic gastoenteropancreatic tumors including carcinoid syndrome, VIPoma, insulinoma, nesidioblastoma, hyperinsulinemia, glucagonoma, gastrinoma and Zollinger-Ellison""s syndrome, GRFoma as well as acute bleeding of the esophageal varices, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, enterocutaneous and pancreatic fistulae but also diarrheas, refractory diarrheas of acquired immunodepression syndrome, chronic secretary diarrhea, diarrhea associated with irritable bowel syndrome, disorders linked with gastrin releasing peptide, secondary pathologies with intestinal grafts, portal hypertension as well as hemorrhages of the varices in patients with cirrhosis, gastrointestinal hemorrhage, hemorrhage of the gastroduodenal ulcer, Crohn""s disease, systemic scleroses, dumping syndrome, small intestine syndrome, hypotension, scleroderma and medullar thyroid carcinoma, illnesses linked with cell hyperproliferation such as cancers and more particularly breast cancer, prostate cancer, thyroid cancer as well as pancreatic cancer and colorectal cancer, fibroses and more particularly fibrosis of the kidney, fibrosis of the liver, fibrosis of the lung, fibrosis of the skin, also fibrosis of the central nervous system as well as that of the nose and fibrosis induced by chemotherapy, and other therapeutic fields such as, for example, cephaleas including cephalea associated with hypophyseal tumors, pain, panic attacks, chemotherapy, cicatrization of wounds, renal insufficiency resulting from delayed development, obesity and delayed development linked with obesity, delayed uterine development, dysplasia of the skeleton, Noonan""s syndrome, sleep apnea syndrome, Graves"" disease, polycystic disease of the ovaries, pancreatic pseudocysts and ascites, leukemia, meningioma, cancerous cachexia, inhibition of H pylori, psoriasis, osteoporosis as well as Alzheimer""s disease.
These diazepines have an affinity and a selectivity for the somatostatin receptors. The clinical applications of natural somatostatin and its peptide analogues are often limited. In fact, a poor bioavailability by oral route and low selectivity are often the main cause (Robinson, C., Drugs of the Future, 1994, 19, 992; Reubi, J. C. et al., TIPS, 1995, 16, 110). Due to their non peptide structure, the compounds of the present invention, agonists or antagonists of somatostatin, appear less susceptible to metabolic degradation than the. natural hormone and its peptide analogues and would thus have a superior duration of action. These compounds can be advantageously used for treating pathological states or the diseases as presented above and in which one (or more) somatostatin receptors are involved.
A subject of the present invention is therefore the compounds of general formula I 
under racemic, or enantiomeric or diastereoisomeric form or mixture thereof, and in which
R1 represents the hydrogen atom or a radical of formula Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94;
Rxe2x80x21 represents an aryl or heteroaryl radical, the aryl and heteroaryl radicals being optionally substituted;
R2 represents a lower alkyl, trifluoromethyl radical or the phenyl radical optionally substituted;
X and Y represent independently O or S;
R3a represents the hydrogen atom, a lower alkyl, hydroxy radical or the radical of formula xe2x80x94OC(O) Rxe2x80x23a;
Rxe2x80x23a represents an alkyl radical containing 1 to 10 carbon atoms optionally substituted;
R3b represents the hydrogen atom or a lower alkyl radical;
R4 represents a radical of formula xe2x80x94(CH2)nxe2x80x94CHRxe2x80x24Rxe2x80x34;
n represents the values 0, 1, 2, 3, 4, 5 or 6;
Rxe2x80x24 and Rxe2x80x34 represent, independently, the hydrogen atom, a lower alkyl, cycloalkyl, lower cycloaklyl alkyl aryl, lower arylalkyl, beteroaryl, lower heteroarylalkyl, arylcarbonyl or adamantyl, radical, these radicals being optionally substituted;
Axe2x80x94B represents xe2x80x94Cxe2x95x90Nxe2x80x94 or xe2x80x94Cxe2x80x94N(R5)xe2x80x94;
R5 represents the hydrogen atom, a lower alkyl, lower alkenyl radical or a radical of formula xe2x80x94C(O)xe2x80x94(CH2)pxe2x80x94Rxe2x80x25;
Rxe2x80x25 represents the hydrogen atom, the radical amino, lower alkyl amino, di(lower alkyl)amino, cycloalkyl, heterocycloalkyl, guanidyl optionally susbtituted by nitro or cyano, aryl optionally substituted, heteroaryl or a radical of formula xe2x80x94NHxe2x80x94C(O)xe2x80x94(CH2)cxe2x80x94NHxe2x80x94C(O)xe2x80x94(CH2)dxe2x80x94NH2;
p represents the values 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
c and d represent independently the values 0, 1, 2 or 3;
or a salt of these compounds.
A more particular subject of the invention is the compounds of general formula I as defined above in which
the substituents, identical or different,of the aryl or heteroaryl radical represented by Rxe2x80x21, are chosen from the following radicals: lower alkyl, lower alkoxy, lower alkylthio, lower alkoxy carbonyl, lower alkyl sulphonyl, halo, trifluoromethyl, trifluoromethyloxy, hydroxy, nitro, cyano, aryl, aryloxy, cycloalkyl or heterocycloalkyl;
the substituents, identical or different, of the phenyl radical represented by R2, are chosen from: the hydroxy, halo radical, a lower alkyl or lower alkoxy radical;
the substituents, identical or different, of the alkyl radical represented by Rxe2x80x23a, are chosen from the following radicals: cycloalkyl; heterocycloalkyl; aryl; heteroaryl; guanidyl optionally substituted by nitro or cyano; a radical of formula NRxe2x80x33aRxe2x80x2xe2x80x33a in which Rxe2x80x33a and Rxe2x80x2xe2x80x33a represent, independently, the hydrogen atom, a lower alkyl, aryl, lower arylalkyl, lower heteroarylalkyl, alkylcarbonyl or alkoxycarbonyl radical;
the susbtitents, identical or different, of alkyl, cycloalkyl, cycloalkyl alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcarbonyl or adamantyl radical represented independently by Rxe2x80x24 and Rxe2x80x34, are chosen from: the hydroxy, halo, trifluoromethyl radical, a lower alkyl or lower alkoxy radical;
the substituents, identical or different, of aryl represented by Rxe2x80x25, are chosen from the following radicals: alkyl or alkoxyalkyl, these radicals alkyl or alkoxyalkyl being optionally substituted by oxy and amino.
In the definitions indicated above, the expression halo represents the fluoro, chloro, bromo or iodo radical, preferably chloro, fluoro or bromo. The expression lower alkyl preferably represents an alkyl radical having 1 to 6 carbon atoms, linear or branched, and in particular an alkyl radical having 1 to 4 carbon atoms such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl radicals, but can also represent a pentyl, isopentyl, hexyl or isohexyl radical.
The lower alkoxy radicals can correspond to the alkyl radicals indicated above such as for example the methoxy, ethoxy, propyloxy or isopropyloxy radicals but also linear, secondary or tertiary butoxy. The terrn lower alkylthio preferably designates the radicals in which the alkyl radical is as defined above such as for example methylthio, ethylthio. The term lower alkenyl preferably designates the alkenyl radical having 1 to 6 carbon atoms such as for example vinyl, allyl, butenyl. The term alkoxyallyl preferably designates the radical in which the alkoxy and alkyl radicals are as defined above.
The term cycloalkyl preferably designates the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl rings. The expression heterocycloalkyl designates a saturated cycloalkyl containing 2 to 7 carbon atoms and at least one heteroatom. This radical can contain several identical or different heteroatoms. Preferably, the heteroatoms are chosen from oxygen, sulphur or nitrogen. As examples of heterocycloalkyl, the following can be mentioned: the pyrrolidine, imidazolidine, pyrrazolidine, isothiazolidine, thiazolidine, isoxazolidine, oxazolidine, piperidine, piperazine or morpholine ring.
The expression aryl represents an aromatic radical, constituted by a ring or condensed rings, such as for example the phenyl or naphthyl radical. The term aryloxy preferably designates the radicals in which the aryl radical is as defined above such as for example the phenoxy radical. The expression heteroaryl designates an aromatic radical, constituted by a ring or condensed rings, with at least one ring containing one or more identical or different heteroatoms chosen from sulphur, nitrogen or oxygem As an example of a heteroaryl radical the following radicals can be mentioned: thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidyl, benzothienyl, benzofuryl and indolyl.
The lower arylalkyl radicals designate the radicals in which respectively the aryl and lower alkyl radicals are as defined above such as for example benzyl, phenethyl or naphthylmethyl. The lower heteroarylalkyl radicals designate the radicals in which respectively the heteroaryl and lower alkyl radicals are as defined above such as for example indolylmethyl, thienylmethyl, fiirylmethyl. The termlower cycloalkyl alkyl designates the radicals in which respectively the cycloalkyl and lower alkyl radicals are as defined above.
The term alkylsulphonyl preferably designates the radicals in which the alkyl radical is as defined above. Similarly, the term arylcarbonyl, alkoxycarbonyl and alkylcarbonyl preferably designate the radicals in which the aryl, alkoxy and alkyl radicals are as defined above. The terms lower alkyl amino and di(lower alkyl) amino preferably designate the radicals in which the radicals alkyl are as defined above such as for example methylamino, ethylamino, dimethylamino, diethylamino or (methyl)(ethyl)amino.
According to the definition of the variable groups, a compound of formula I as defined above can have one or more asymmetrical carbons. The invention relates to the compounds of formula I as defined above, which compounds can be found in racemic, enantiomeric or diastereoisomeric form or a mixture thereof.
A more particular subject of the invention is the compounds of general formula I as defined above in which
Rxe2x80x21 represents an aryl radical optionally substituted by one or more substituents, identical or different, chosen from the following radicals: lower alkoxy, trifluoromethyl or nitro;
R2 represents a lower alkyl radical or the radical phenyl optionally substituted by one or more groups, identical or different, chosen from halo or lower alkyl;
R3a represents the hydrogen atom, hydroxy or the radical of formula xe2x80x94C(O)Rxe2x80x23a;
Rxe2x80x23a represents a linear or branched alkyl containing 1 to 6 carbon atoms optionally substituted by one or more substituents, identical or different, of formula NRxe2x80x33aRxe2x80x2xe2x80x33a in which Rxe2x80x33a and Rxe2x80x2xe2x80x33a represent, independently, the hydrogen atom, a lower alkyl or alkoxycarbonyl.
R3b represents the hydrogen atom;
Rxe2x80x24 and Rxe2x80x34 represent, independently, the hydrogen atom, a lower alkyl, cycloalkyl, aryl, heteroaryl, arylcarbonyl or adamantyl radical;
Axe2x80x94B represents xe2x80x94Cxe2x95x90N,
and in a preferred manner,
Rxe2x80x21 represents a phenyl radical optionally substituted by one or more substituents, identical or different, chosen from the following radicals: lower alkoxy, tifluoromethyl or nitro;
R2 represents a lower alkyl radical or the phenyl radical optionally substituted by one or more groups, identical or different, chosen from: methyl, chloro or fluoro;
Rxe2x80x23a represents a linear or branched alkyl containing 1 to 6 carbon atoms optionally substituted by one or more amino groups;
Rxe2x80x24 and Rxe2x80x34 represent, independently, the hydrogen atom, lower alkyl, cyclohexyl, phenyl, pyridyl, phenylcarbonyl or adamantyl;
More particularly, a subject of the invention is the compounds described hereafter in the examples and in which Axe2x80x94B represents xe2x80x94Cxe2x95x90Nxe2x80x94, in particular the compounds in which the R1; Rxe2x80x21; Y; R2; R3a; R3b; X; n; Rxe2x80x24; Rxe2x80x34 radicals respectively have the following meanings:
H;-;-; 2-Cl-Phe; H; H; O; 1; H; Phe;
H;-;-; 2-Cl-Phe; H; H; S; 1; H; Phe;
H;-;-; 2-Cl-Phe; H; H; O; 2; H; Phe;
H;-;-; 2-Cl-Phe; H; H; O; 0; H; phenylcarbonyl;
H;-;-; 2-Cl-Phe; H; H; O; 0; H; Phe;
H;-;-; 2-Cl-Phe; H; H; O; 0; H; cyclohexyl;
H;-;-; 2-Cl-Phe; H; H; O; 4; H; H;
H;-;-; 2-Cl-Phe; H; H; O; 2; Phe; Phe;
H;-;-; 2-Cl-Phe; H; H; O; 2; Me; Me;
H;-;-; 2-Cl-Phe; H; H; O; 0; H; adamantyl;
H;-;-; 2-Cl-Phe; H; H; O; 1; H; pyridyl;
H;-;-; Phe; H; H; O; 1; H; Phe;
H;-;-; 4-Cl-Phe; H; H; O; 1; H; Phe;
H;-;-; 2-F-Phe; H; H; O; 1; H; Phe;
H;-;-; 4-F-Phe; H; H; O; 1; H; Phe;
H;-;-; 2-Me-Phe; H; H; O; 1; H; Phe;
H;-;-; t-butyl; H; H; O; 1; H; Phe;
H;-;-; 2-Cl-Phe; OH; H; O; 1; H; Phe;
H;-;-; 2-Cl-Phe; OC(O)xe2x80x94(CH2)6NH2; H; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 2; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; S; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 0; H; phenylcarbonyl;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 0; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 4; H; H;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 0; H; cyclohexyl;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 2; Phe; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 2; Me; Me;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 0; H; adamantyl;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 1; H; pyridyl;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; Phe; H; H; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 4-Cl-Phe; H; H; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-F-Phe; H; H; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 4-F-Phe; H; H; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-F3C-Phe; O; 4-F-Phe; H; H; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Me-Phe; H; H; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; t-butyl; H; H; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; OH; H; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; xe2x80x94OC(O)xe2x80x94(CH2)6NH2; H; O; 1; H; Phe;
A more particular subject of the invention is the compounds of general formula I as defined above in which
Rxe2x80x21 represents an aryl radical optionally substituted by one or more substituents, identical or different, chosen from the following radicals: lower alkoxy or nitro;
R2 represents a phenyl radical optionally substituted by one or more identical or different halo groups;
R3a and R3b represent the hydrogen atom;
Rxe2x80x24 and Rxe2x80x34 represent, independently, the hydrogen atom, a lower alkyl or aryl radical;
Axe2x80x94B represents xe2x80x94Cxe2x80x94N(R5)xe2x80x94;
R5 represents the hydrogen atom, a lower alkenyl radical or a radical of formula xe2x80x94C(O)xe2x80x94(CH2)pxe2x80x94Rxe2x80x25;
and in a preferred manner,
Rxe2x80x21 represents a phenyl radical optionally substituted by one or more substituents, identical or different, chosen from the following radicals: lower alkoxy or nitro;
R2 represents a lower alkyl or phenyl radical optionally substituted by a chloro group;
Rxe2x80x24 and Rxe2x80x34 represent, independently, the hydrogen atom, lower alkyl or phenyl;
R5 represents the hydrogen atom, pentenyl or a radical of formula xe2x80x94C(O)xe2x80x94Rxe2x80x25;
Rxe2x80x25 represents the hydrogen atom, a radical amino, cyclopentyle, indolyle, of formula xe2x80x94NHxe2x80x94C(O)xe2x80x94CH2xe2x80x94NHxe2x80x94C(O)xe2x80x94CH2xe2x80x94NH2, or phenyl optionally substituted by one or more substituents, identical or different, chosen from alkyl and alkoxyalkyl radicals, these radicals alkyl and alkoxyalkyl being optionally substituted by oxy and amino.
More particularly, a subject of the invention is the compounds described hereafter in the examples and in which Axe2x80x94B represents xe2x80x94Cxe2x80x94N(R5), in particular the compounds in which the R1; Rxe2x80x21; Y; R2; R3a; R3b; X; R5; n; Rxe2x80x24; Rxe2x80x34 radicals respectively have the following meanings:
H;-;-; 2-Cl-Phe; H; H; H; O; 1; H; Phe;
H;-;-; 2-Cl-Phe; H; H; H; O; 2; Me; Me;
H;-;-; 2-Cl-Phe; H; H; xe2x80x94CH2CHxe2x95x90C(Me)2; O; 1; H; Phe;
H;-;-; 2-Cl-Phe; H; H; aminohexylcarbonyl; O; 1; H; Phe;
H;-;-; 2-Cl-Phe; H; H; aminopentylcarbonyl; O; 1; H; Phe;
H;-;-; 2-Cl-Phe; H; H; indolylmethylcarbonyl; O; 1; H; Phe;
H;-;-; 2-Cl-Phe; H; H; aminobutylcarbonyl; O; 1; H; Phe;
H;-;-; 2-Cl-Phe; H; H; propylcarbonyl; O; 1; H; Phe;
H;-;-; 2-Cl-Phe; H; H; cyclopentyl-methylcarbonyl; O; 1; H; Phe;
H;-;-; 2-Cl-Phe; H; H; phenyl-propylcarbonyl; O; 1; H; Phe;
H;-;-; 2-Cl-Phe; H; H; phenylethylcarbonyl; O; 1; H; Phe;
H;-;-; 2-Cl-Phe; H; H; 4-(L-alanoyloxymethyl)benzyl carbonyl; O; 1; H; Phe;
H;-;-; 2-Cl-Phe; H; H; 4-aminomethyl-phenylcarbonyl; O; 1; H; Phe;
H;-;-; Phe; H; H; NH2xe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94CH2xe2x80x94C(O)xe2x80x94; O; 2; Me; Me;
H;-;-; neopentyl; H; H; aminohexylcarbonyl; O; 1; H; Phe;
H;-;-; isobutyl; H; H; aninohexylcarbonyl; O; 1; H; Phe;
H;-;-; isobutyl; H; H; H; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; H; O; 4; H; H;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; xe2x80x94CH2CHxe2x95x90C(Me)2; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; aminohexylcarbonyl; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; propylcarbonyl; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; cyclopentyl-methylcarbonyl; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; phenyl-propylcarbonyl; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; phenylethylcarbonyl; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; arminobutylcarbonyl; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; indolylmethylcarbonyl; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; aminopentylcarbonyl; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; Phe; H; H; NH2xe2x80x94CH2xe2x80x94C(O)NHxe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94CH2xe2x80x94C(O)xe2x80x94; O; 2; Me; Me;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; Phe; H; H; aminohexylcarbonyl; O; 2; Me; Me;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; neopentyl; H; H; aminohexylcarbonyl; O; 1; H; Phe;
Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94; 2-NO2-4-MeO-Phe; S; isobutyl; H; H; aminohexylcarbonyl; O; 1; H; Phe.
A compound of formula (I) according to the invention and in which Axe2x80x94B represents Cxe2x95x90N, R1 the hydrogen atom and R3a the hydrogen atom or an alkyl radical, can be obtained by reacting a compound of formula (1) 
in which R2, R3a R3b have the meaning indicated above and Rxe2x80x3 represents a lower alkyl or lower arylalkyl radical, with a compound R4Z in which R4 has the meaning indicated above and Z represents a parting group, in the presence of a strong base, in order to obtain compound (2) 
in which X represents the oxygen atom, compound (2) thus obtained which can be reacted with a thiation reagent in order to obtain compound (2) in which X represents a sulphur atom, compound (2) in which X represents an oxygen or sulphur atom, which is finally subjected to a deprotection reaction of the carbamate in order to obtain the desired product (I).
During the preparation of compounds (2) in which X represents the oxygen atom, the compounds of formula (1) are subjected to the action of a strong base such as for example sodium hydride in an inert solvent such as for example tetrahydrofuran or dimethylformamide at a temperature around 20xc2x0 C. Compound R4Z is then added to the reaction medium at a temperature around 20xc2x0 C. then the reaction medium is heated to about 80xc2x0 C. The parting group Z of compound R4Z, can be for example a mesylate, tosylate or a halogen atom (preferably a chlorine or bromine atom). The preparation of compounds (2) in which X represents the sulphur atom starting from the compounds (2) in which X represents the oxygen atom, can be implemented at a temperature around 80xc2x0 C. with a thiation agent such as phosphorus pentasulphide in a solvent such as pyridine.
The deprotection of the carbamate which does not affect the remainder of the molecule, can be carried out according to the known deprotection methods (T. W. Greene et al., Protective Groups in Organic Synthesis, Wiley-Interscience, 1991). Thus, in the case Iwhere Rxe2x80x3 represents a linear alkyl group (such as ethyl) or an arylalkyl group (such as benzyl), the deprotection of the carbamate can be implemented by agitating the reaction medium at ambient temperature in a strongly acid medium such as, for example, in the hydrobromic acid (33% in acetic acid). In the case where Rxe2x80x3 represents a more hindered alkyl group (such as t-butyl), the reaction can be implemented in the trifluoroacetic acid in an inert solvent such as dichloromethane at a temperature around 20xc2x0 C.
The products of formula (1) can be prepared according to the method described in the Patent FR2645153 or according to similar methods.
Certain products of formula R4Z are in general commercially available (for example from the firms Acros or Aldrich); the others can be prepared from the alcohol of formula R4xe2x80x94OH in an inert solvent such as dichloromethane by the action for example of tosyl chloride in the presence of triethylamine or by the action of triphenylphosphine and carbon tetrabromide.
A compound of formula (I) according to the invention and in which Axe2x80x94B represents Cxe2x95x90N, R1 the hydrogen atom and R3a the hydroxy radical, can be obtained by oxidation of a compound of formula (2) as defined above, in an inert solvent in order to obtain a compound of formula (3) 
in which R2, R3b, R4, Rxe2x80x3 and X have the meaning indicated above,
which compound of formula (3) is treated with acetic anhydride in order to obtain a compound of formula (4) 
in which R2, R3b, R4, Rxe2x80x3 and X have the meaning indicated above,
which compound (4) is then saponified in order to obtain the compound of formula (5) 
in which R2, R3b, R4, Rxe2x80x3 and X have the meaning indicated above,
which compound (5) is finally subjected to a deprotection reaction of the carbamate in order to obtain the corresponding compound of formula (I) in which R1 represents H and R3a the hydroxy radical.
The oxidation of compound (2) at the level of the jinine of the diazepine, can be carried out by the action of an organic oxidizing agent such as for example metachioroperoxybenzoic acid, at a temperature around 20xc2x0 C., in an inert solvent such as dichloromethane or 1,2-dichloroethane. The reaction of compound (3) with acetic anhydride is a Polonowski type rearrangement (Gilman N. W. et al., J. Am. Chem. Soc. 1990, 112, 3969-3978) which can be implemented at a temperature around 70xc2x0 C. The saponification reaction of compound (4) can be carried out by the action of a mineral base such as for example sodium hydroxide or lithium hydroxide, in a lower aliphatic alcohol (methanol, ethanol for example), at a temperature around 20xc2x0 C.
A compound of formula (I) according to the invention and in which Axe2x80x94B represents Cxe2x95x90N, R1 the hydrogen atom and R3a an xe2x80x94OC(O)xe2x80x94Rxe2x80x23a radical, can be obtained by reacting a compound of formula (5) as defined above, with an acid of formula Rxe2x80x23aC(O)OH in which Rxe2x80x23a has the meaning indicated above, in order to obtain a compound of formula (6) 
in which R2, Rxe2x80x23a, R3b, R4, Rxe2x80x3 and X have the meaning indicated above, which compound (6) is finally subjected to a deprotection reaction of the carbamate in order to obtain the corresponding compound of formula (I) in which R1 represents H and R3a the xe2x80x94OC(O)Rxe2x80x23a radical.
The conversion of compound (5) into compound (6) can be carried out under conditions similar to those of esterification reactions, known to a person skilled in the art; thus it can be implemented at a temperature around 20xc2x0 C. in an inert solvent such as dichloromethane or 1,2-dichloroethane.
The compounds of formula I according to the invention in which Axe2x80x94B represents Cxe2x95x90N, R1 a radical of formula Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94, can be prepared according to the process which consists of reacting the corresponding compound of formula (I) in which R1 represents the hydrogen atom, with a compound of formula
Rxe2x80x21xe2x80x94Nxe2x95x90Cxe2x95x90Yxe2x80x83xe2x80x83(7)
in which Rxe2x80x21 and Y have the meaning indicated above, in order to form the chosen compound of formula I.
During the preparation of the compound of formula I in which R1 represents a radical of formula Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94, the addition of the compound of formula (7), to the compound of formula (I) in which R1 represents the hydrogen atom, is easily carried out at a temperature around 20xc2x0 C. in a chlorinated solvent such as dichloromethane or 1,2-dichloroethane. The products of formula (7) are in the main commercially available or can be prepared by reacting the corresponding amine with (thio)phosgene according to methods known to a person skilled in the art.
A compound of formula (I) according to the invention and in which Axe2x80x94B represents xe2x80x94Cxe2x80x94N(R5)xe2x80x94, R1 and R5 a hydrogen atom and R3a the hydrogen atom or an alkyl radical, can be obtained by the action of a gentle reducing agent in acid medium, on a compound of formula (2) as defined above, in order to obtain the compound of formula (8) 
in which R2, R3a, R3b, R4, X and Rxe2x80x3 have the meaning indicated above, which compound (8) is subjected to a deprotection reaction of the carbamate in order to obtain the desired product (I) in which R1 represents the hydrogen atom.
During the reduction of compound (2) to obtain compound (8), a gentle reducing agent can be used such as sodium cyanoborohydride in a solvent such as a lower alcoholic solvent (methanol, ethanol for example) at a temperature around 20xc2x0 C.
A compound of formula (1) according to the invention and in which Axe2x80x94B represents Cxe2x80x94NR5, R1 represents a hydrogen atom, R3a the hydrogen atom or the alkyl radicals and R5 represents a alkenyl radical, can be obtained by reacting a compound of formula (8) as defined above, with a compound of formula Zxe2x80x2R5 in which R5 has the meaung indicated above and Zxe2x80x2 represents a parting group, in the presence of a strong mineral base in an inert solvent, in order to obtain compound (9) 
in which R2, R3a, R3b, R4, X, Rxe2x80x3 and R5 have the meaning indicated above,
which compound (9) is subjected to a deprotection reaction of the carbamate in order to obtain the desired product (I) in which R1 represents the hydrogen atom.
The preparation of compound (9) starting from compound (8), can be implemented by the action of sodium hydride in a solvent such as tetrahydrofuran at a temperature around 60xc2x0 C. The parting group Zxe2x80x2 of compound Zxe2x80x2R5 can be a mesylate, tosylate or a halogen atom.
A compound of formula (1) according to the invention and in which Axe2x80x94B represents xe2x80x94Cxe2x80x94N(R5)xe2x80x94, R1 represents a hydrogen atom, R3a the hydrogen atom or the alkyl radical and R5 represents an xe2x80x94C(O)xe2x80x94(CH)pxe2x80x94Rxe2x80x25 radical, can be obtained by reacting a compound of formula (8) as defined above, with an acid of formula Rxe2x80x25xe2x80x94(CH2)pxe2x80x94C(O)OH in which Rxe2x80x25 and p have the meaning indicated above, in order to obtain the corresponding compound (10), 
in which R2, R3a, R3b, R4, X, Rxe2x80x3, p and Rxe2x80x25 have the meaning indicated above,
which compound (10) is subjected to a deprotection reaction of the carbamate in order to obtain the desired product (I) in which R1 represents the hydrogen atom.
The reaction of compound Rxe2x80x25xe2x80x94(CH2)pxe2x80x94C(O)OH with compound (8) can be carried out under conditions similar to peptide coupling reactions. It can be implemented at a temperature around 20xc2x0 C. in an inert solvent such as dichloromethane or 1,2-dichloroethane.
A compound of formula (I) according to the invention and in which Axe2x80x94B represents xe2x80x94Cxe2x80x94N(R5)xe2x80x94, R1 the hydrogen atom and R3a the hydroxy radical, can be obtained by reduction of the compound of formula (4), in order to obtain the compound of formula (11) 
in which R2, R3b, R4, X and Rxe2x80x3 have the meaning indicated above,
which compound (11) is
either subjected to a saponification reaction then to a deprotection reaction of the carbamate in order to obtain the desired product (I) in which R1 and R5 represent the hydrogen atom;
or treated with a compound of formula halo-R5 in which R5 represents an alkenyl radical or an acid of formula Rxe2x80x25xe2x80x94(CH2)pxe2x80x94C(O)OH in which Rxe2x80x25 and p have the meaning indicated above, in order to obtain the compound of formula (12) 
in which R2, R3b, R4, X and Rxe2x80x3 have the meaning indicated above and R5 represents respectively an alkenyl radical or Rxe2x80x25CH2)pxe2x80x94C(O)xe2x80x94,
which compound (12) is finally subjected to a saponification reaction then a deprotection reaction of the carbamate in order to obtain the desired product (I) in which R1 represents the hydrogen atom and R5 an alkenyl radical or Rxe2x80x25xe2x80x94(CH2)pxe2x80x94C(O)xe2x80x94.
A compound of formula (I) according to the invention and in which Axe2x80x94B represents xe2x80x94Cxe2x80x94N(R5)xe2x80x94, R1 the hydrogen atom and R3a an xe2x80x94OC(O)xe2x80x94Rxe2x80x23a radical, can be obtained by reduction of the compound of formula (6), in order to obtain a compound of formula (13) 
in which R2, Rxe2x80x23a, R3b, R4, X and Rxe2x80x3 have the meaning indicated above,
which compound (13) is
either subjected to a deprotection reaction of the carbamate in order to obtain the desired product (I) in which R1 and R5 represent the hydrogen atom;
or treated with a compound halo-R5 in which R5 represents an alkenyl radical or an acid of formula Rxe2x80x25xe2x80x94(CH2)pxe2x80x94C(O)OH in which Rxe2x80x25 and p have the meaning in indicated above, in order to obtain the compound of formula (14) 
in which R2, Rxe2x80x23a, R3b, R4, X and Rxe2x80x3 have the meaning indicated above and R5 represents respectively an alkenyl radical or Rxe2x80x25xe2x80x94(CH2)pxe2x80x94C(O)xe2x80x94,
which compound (14) is finally subjected to a deprotection reaction of the carbamate in order to obtain the desired product (I) in which R1 represents the hydrogen atom and R5 respectively an alkenyl radical or Rxe2x80x25xe2x80x94(CH2)pxe2x80x94C(O)xe2x80x94.
The conditions for adding the radical R5 (different firm H) to the nitrogen atom of diazepines (11) and (13) are identical to the reaction conditions for the preparation of compounds (9) and (10). The deprotection reactions of the carbamates (5), (6), (8), (9), (10), (13) and (14) are as defined previously; the Rxe2x80x3 radical is chosen according to the other fumctions present in the molecule and with the aim of obtaining a selective deprotection of the carbamate group Rxe2x80x3OC(O)Nxe2x80x94.
The compounds of formula I according to the invention in which Axe2x80x94B represents xe2x80x94Cxe2x80x94N(R5)xe2x80x94 and R1 represents a radical of formula Rxe2x80x21xe2x80x94NHxe2x80x94C(Y)xe2x80x94, can be prepared by the action of a compound of formula (7) Rxe2x80x21xe2x80x94Nxe2x95x90Cxe2x95x90Y in which Rxe2x80x2, and Y have the meaning indicated above, on the corresponding compound of formula (I) in which R1 represents the hydrogen atom, in order to form the chosen compound of formula I.
The compounds of formula (2) are new. A subject of the invention is also, as new industrial products, and in particular as new industrial products intended for the preparation of the compounds of formula (I) according to the invention, the products of formula (2).
The compounds I of the present invention have useful pharmacological properties. Thus it was discovered that the compounds I of the present invention have a high affinity for one (or more) of the somatostatin receptors. They can be used as non-peptide agonists or antagonists of somatostatin in a selective or non-selective manner.
The compounds of the present invention can therefore be used in different therapeutic applications. They can advantageously be used for treating the pathological states or diseases as presented above and in which one (or more) of the somatostatin receptors are involved.
An illustration of the pharmacological properties of the compounds of the invention will be found hereafter in the experimental part.
A subject of the present Application is also, as medicaments, the products of formula I as defined above, as well as the addition salts with pharmaceutically acceptable mineral or organic acids of said products of formula I, as well as the pharmaceutical compositions containing, as active ingredient, at least one of the medicaments as defined above, in combination with a pharmaceutically acceptable support
The pharmaceutical composition can be in solid form, for example, powders, granules, tablets, gelatin capsules or suppositories. The appropriate solid supports can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
The pharmaceutical compositions containing a compound according to the invention can also be presented in liquid form such as, for example, solutions, emulsions, suspensions or syrups. The appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, similarly their mixtures, in varied proportions, in water, with phannaceutically acceptable oils or greases added to them. Sterile liquid compositions can be used for intramuscular, intaperitoneal or subcutaneous injections and sterile compositions can also be administered intravenously.
All the technical and scientific terms used in the present text have the meanings known to a person skilled in the art. Similarly, all patents (or patent applications) as well as other bibliographical references are incorporated by way of reference.
The following examples are presented to illustrate dte above procedures and must in no case be considered as a limit to the scope of the invention.